Downregulation of miR-146a inhibits influenza A virus replication by enhancing the type I interferon response in vitro and in vivo - 16/02/19
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Graphical abstract |
In this article, we investigated the role of miR-146a in IAV replication in vitro and in vivo. In vitro, we found overexpression of miR-146a promoted IAV replication, while downregulation of miR-146a repressed replication. Moreover, we found that miR-146a diminished type I interferon (IFN) responses by directly targets tumor necrosis factor receptor association factor 6 (TRAF6). In vivo, inhibition of miR-146a alleviated IAV-induced mice lung injury and promoted survival rates by promoting type I antiviral activities. It is, therefore, concluded that downregulation of miR-146a inhibits IAV replication by enhancing type I IFN response through its target gene TRAF6 in vitro and in vivo, suggesting miR-146a antagomir might be a potential therapeutic target during IAV infection.
Highlights |
• | miR-146a was significantly induced in IAV infected A549 cells. |
• | miR-146a enhanced viral replication via inhibiting type I IFN production. |
• | Inhibition of miR-146a alleviated IAV-induced lung injury in mice. |
Abstract |
Albeit microRNAs (miRNAs) have become increasingly appreciated for their essential roles in innate immune responses to viral infections; however, it is unknown how host miRNAs regulate influenza A virus (IAV)-induced inflammation. The aim of our study was to investigate the role of miR-146a in IAV replication in vitro and in vivo. In vitro, we found miR-146a was significantly upregulated in A549 cells with IAV infection. Overexpression of miR-146a promoted IAV replication, while downregulation of miR-146a repressed replication. We found that miR-146a diminished type I interferon (IFN) responses by decreasing IFN-β production and IFN-stimulated gene (ISG) expression. Furthermore, we found the IFNs level and IAV replication regulated by miR-146a inhibitor was partially reversed by depletion of interferon receptor (IFNAR) 1 or 2. In addition, we found that miR-146a directly targets tumor necrosis factor receptor association factor 6 (TRAF6), which is involved in the production of type I IFN, and TRAF6 overexpression reversed the replication-promoting effect of miR-146a on IAV. In vivo, inhibition of miR-146a alleviated IAV-induced mice lung injury and promoted survival rates by promoting type I antiviral activities. It is, therefore, concluded that downregulation of miR-146a inhibits IAV replication by enhancing type I IFN response through its target gene TRAF6 in vitro and in vivo, suggesting miR-146a antagomir might be a potential therapeutic target during IAV infection.
Le texte complet de cet article est disponible en PDF.Keywords : miR-146a, Influenza A virus, TRAF6, Type I IFN response
Plan
Vol 111
P. 740-750 - mars 2019 Retour au numéro
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